Zhicai Shang

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Name: 商志才; Shang, ZhiCai

Organization: Zhejiang University , China

Department: Department of Chemistry

Title: Professor(PhD)

Chemicals
References

Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides

Co-reporter:Hua Yu;Mao-jun Wang;Nan-xia Xuan

Journal of Zhejiang University-SCIENCE B 2015 Volume 16( Issue 10) pp:883-896

Publication Date(Web):2015 October

DOI:10.1631/jzus.B1500106

To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 (EHD1 EH domain) with three peptides containing NPF (asparagine-proline-phenylalanine), DPF (aspartic acid-proline-phenylalanine), and GPF (glycine-proline-phenylalanine) motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated.Molecular dynamics (MD) simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/generalized Born surface area (MM/GBSA) method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software.The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the structural basis of contributions of van der Waals interactions of the flanking residues to the binding.van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.从结构和能量两个角度, 探究EHD1 蛋白中的Eps15 同源结构域与不同肽链之间形成的复合物之间的亲和力差异的原因, 为肽类抑制剂设计提供关键信息。通过分子动力学模拟的方法, 详细分析了三个复合物的结构差异。通过结合自由能计算及能量分解, 定量对比了三条肽链中各个残基对复合物形成的贡献, 确定了范德华相互作用以及侧面残基的氢键是影响亲和力大小的关键因素。用GROMACS 程序对EHD1 蛋白中的Eps15 同源结构域与肽链形成的三个复合物进行各60 纳秒的分子动力学模拟, 用AMBER 程序中的MM/GBSA 方法进行结合自由能计算和能量分解, 用FoldX 软件对三个复合物进行丙氨酸扫描实验。在对EHD1 蛋白中的Eps15 同源结构域进行高亲和力的肽类抑制剂设计时, 范德华相互作用应该成为主要考虑因素。与蛋白质形成氢键的能力是侧面残基选择的参考因素。

Indirect Readout in Protein-Peptide Recognition: A Different Story from Classical Biomolecular Recognition

Co-reporter:Hua Yu, Peng Zhou, Maolin Deng, and Zhicai Shang

Journal of Chemical Information and Modeling 2014 Volume 54(Issue 7) pp:2022-2032

Publication Date(Web):July 7, 2014

DOI:10.1021/ci5000246

Protein-peptide interactions are prevalent and play essential roles in many living activities. Peptides recognize their protein partners by direct nonbonded interactions and indirect adjustment of conformations. Although processes of protein-peptide recognition have been comprehensively studied in both sequences and structures recently, flexibility of peptides and the configuration entropy penalty in recognition did not get enough attention. In this study, 20 protein-peptide complexes and their corresponding unbound peptides were investigated by molecular dynamics simulations. Energy analysis revealed that configurational entropy penalty introduced by restriction of the degrees of freedom of peptides in indirect readout process of protein-peptide recognition is significant. Configurational entropy penalty has become the main content of the indirect readout energy in protein-peptide recognition instead of deformation energy which is the main source of the indirect readout energy in classical biomolecular recognition phenomena, such as protein–DNA binding. These results provide us a better understanding of protein-peptide recognition and give us some implications in peptide ligand design.

Metal-free C–N bond-forming reaction: straightforward synthesis of anilines, through cleavage of aryl C–O bond and amide C–N bond

Co-reporter:Jianzhong Yu, Peizhi Zhang, Jun Wu, Zhicai Shang

Tetrahedron Letters 2013 Volume 54(Issue 24) pp:3167-3170

Publication Date(Web):12 June 2013

DOI:10.1016/j.tetlet.2013.04.028

An efficient metal-free C–N bond forming reaction through cleavage of aryl C–O bond and amide C–N bond has been developed. This process represents a practical method for the facile construction of anilines with a broad substrate scope and wide functional group tolerance in moderate to excellent yields.

A General and Efficient CuBr2-Catalyzed N-Arylation of Secondary Acyclic Amides

Co-reporter:Mangang Wang;Hua Yu;Xinwen You;Jun Wu

Chinese Journal of Chemistry 2012 Volume 30( Issue 10) pp:2356-2362

Publication Date(Web):

DOI:10.1002/cjoc.201200701

Abstract

A general and efficient Cu(II)-catalyzed cross-coupling method is reported for the preparation of acyclic tertiary amides. Generally moderate to excellent yields and functional group tolerance were obtained with secondary acyclic amides and aryl halides as substrates in toluene.

Prediction of protein 13Cα NMR chemical shifts using a combination scheme of statistical modeling and quantum-mechanical analysis

Co-reporter:Xiuhong Liu, Yanrong Ren, Peng Zhou, Zhicai Shang

Journal of Molecular Structure 2011 Volume 995(1–3) pp:163-172

Publication Date(Web):31 May 2011

DOI:10.1016/j.molstruc.2011.04.012

Quantitative structure–property relationships (QSPRs) on the basis of constitutional, topological, geometrical, and electrostatic descriptors are developed for 2454 13Cα NMR chemical shifts of 21 structure-known, high-quality monomeric proteins. In this procedure, heuristic approach is employed to perform variable-selection for obtaining few independent and significant descriptors. Coupled with various machine learning methods, including MLR, PLS, LSSVM, RF, and GP, these selected variables are then used to create both linear and nonlinear statistical models with the experimentally determined 13Cα NMR chemical shifts of proteins. In addition, the secondary structural effect and environmental influence on protein chemical shifts are also investigated in detail through structural survey and quantum-mechanical calculations. We demonstrate that (i) relationship between 13Cα NMR chemical shifts and local structural features is, to some extent, nonlinear, and (ii) the 13Cα chemical shift values are not only determined by corresponding side-chain conformations, but also affected from the arrangement and configuration of spatially vicinal residues.Highlights► We use five methods to develop accurate statistical models for 13Cα NMR chemical shifts of proteins. ► We examine the secondary structural and local environmental influence on chemical shifts. ► We investigate the cause of the deviation between real and ideal chemical shift for amino acids. ► The nonlinear methods are generally better than the linear methods, especially the RF method. ► An amino acid in different local environment in protein have different chemical shift.

Halogen-Ionic Bridges: Do They Exist in the Biomolecular World?

Co-reporter:Peng Zhou, Yanrong Ren, Feifei Tian, Jianwei Zou and Zhicai Shang

Journal of Chemical Theory and Computation 2010 Volume 6(Issue 7) pp:2225-2241

Publication Date(Web):June 2, 2010

DOI:10.1021/ct100167w

If considering that the pronouncedly charged halide anions are ubiquitous in the biological world, then it is interesting to ask whether the halogen-ionic bridges—this term is named by us to describe the interaction motif of a nonbonded halogen ion with two or more electrophiles simultaneously—commonly exist in biomolecules and how they contribute to the stability and specificity of biomolecular folding and binding? To address these problems, we herein present a particularly systematic investigation on the geometrical profile and the energy landscape of halogen ions interacting with and bridging between polar and charged molecular moieties in small model systems and real crystal structures, by means of ab initio calculation, database survey, continuum electrostatic analysis, and hybrid quantum mechanics/molecular mechanics examination. All of these unequivocally demonstrate that this putative halide motif is broadly distributed in biomolecular systems (>6000) and can confer a substantial stabilization for the architecture of proteins and their complexes with nucleic acids and small ligands. This stabilization energy is estimated to be generally more than 100 kcal·mol−1 for gas-phase states or about 20 kcal·mol−1 for solution conditions, which is much greater than that found in sophisticated water-mediated (<10 kcal·mol−1) and salt (∼ 3.66 kcal·mol−1) bridges. In this respect, we would expect that the proposed halogen-ionic bridge, which has long been unrecognized in the arena of biological repertoires, could be appreciated in chemistry and biology communities and might be exploited as a new and versatile tool for rational drug design and bioengineering.

Systematic Classification and Analysis of Themes in Protein−DNA Recognition

Co-reporter:Peng Zhou, Feifei Tian, Yanrong Ren and Zhicai Shang

Journal of Chemical Information and Modeling 2010 Volume 50(Issue 8) pp:1476-1488

Publication Date(Web):July 23, 2010

DOI:10.1021/ci100145d

Protein−DNA recognition plays a central role in the regulation of gene expression. With the rapidly increasing number of protein−DNA complex structures available at atomic resolution in recent years, a systematic, complete, and intuitive framework to clarify the intrinsic relationship between the global binding modes of these complexes is needed. In this work, we modified, extended, and applied previously defined RNA-recognition themes to describe protein−DNA recognition and used a protocol that incorporates automatic methods into manual inspection to plant a comprehensive classification tree for currently available high-quality protein−DNA structures. Further, a nonredundant (representative) data set consisting of 200 thematically diverse complexes was extracted from the leaves of the classification tree by using a locally sensitive interface comparison algorithm. On the basis of the representative data set, various physical and chemical properties associated with protein−DNA interactions were analyzed using empirical or semiempirical methods. We also examined the individual energetic components involved in protein−DNA interactions and highlighted the importance of conformational entropy, which has been almost completely ignored in previous studies of protein−DNA binding energy.

A Green and Novel Method of Synthesizing 2,2-Arylmethylene Bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) Catalyzed by L-Histidine in Ionic Liquid

Co-reporter:Yan Zhang

Chinese Journal of Chemistry 2010 Volume 28( Issue 7) pp:1184-1188

Publication Date(Web):

DOI:10.1002/cjoc.201090205

Abstract

An efficient and green approach to the synthesis of 2,2′-arylmethylene bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) using L-histidine as the catalyst is described. In addition, room temperature ionic liquid 1-butyl-3-methylimidazonium tetrafluoroborate [bmim]BF₄ was used as green recyclable alternatives to volatile organic solvents for this condensation reaction. This green catalytic system can be recycled several times with no decreases in yields and reaction rates.

Catalysis by L-Lysine: A Green Method for the Condensation of Aromatic Aldehydes with Acidic Methylene Compounds in Water at Room Temperature

Co-reporter:Yan Zhang;Cuizhi Sun;Jun Liang ; Dr. Zhicai Shang

Chinese Journal of Chemistry 2010 Volume 28( Issue 11) pp:2255-2259

Publication Date(Web):

DOI:10.1002/cjoc.201090373

Abstract

The condensation of aromatic aldehydes with acidic methylene compounds such as ethyl benzoylacetate, 2,4-pentanedione and dimedone proceeded efficiently in pure water in the presence of L-lysine at room temperature. Interestingly, there are two different reaction mechanisms taking place under the same green catalyst system. This provides a green and mild synthetic method for the preparation of these two classes of compounds.

Fast and Eco-friendly Synthesis of Dipyrromethanes by H2SO4SiO2 Catalysis under Solvent-free Conditions

Co-reporter:Yan Zhang;Jun Liang

Chinese Journal of Chemistry 2010 Volume 28( Issue 2) pp:259-262

Publication Date(Web):

DOI:10.1002/cjoc.201090063

Abstract

For the first time, sillica-supported sulfuric acid has been used as a heterogeneous, reusable and efficient catalyst at room temperature to give the corresponding dipyrromethanes in a very short reaction time. The new reaction procedure is simple and solvent is not required.

Do Halide Motifs Stabilize Protein Architecture?

Co-reporter:Peng Zhou, Feifei Tian, Jianwei Zou, Yanrong Ren, Xiuhong Liu, and Zhicai Shang

The Journal of Physical Chemistry B 2010 Volume 114(Issue 47) pp:15673-15686

Publication Date(Web):November 4, 2010

DOI:10.1021/jp105259d

Halide anions are traditionally recognized as the structure maker and breaker of bulk water to indirectly influence the physicochemical and biological properties of biomacromolecules immersed in electrolyte solution, but here we are more interested in whether they can be structured in the protein interior, forming that we named “halide motifs”, to stabilize the protein architecture through direct noncovalent interactions with their context. In the current work, we present a systematical investigation on the energy components in 782 high-quality protein halide motifs retrieved from the Protein Data Bank (PDB), by means of the continuum electrostatic analysis coupled with nonelectrostatic considerations, as well as hybrid quantum mechanical/molecular mechanical (QM/MM) examination. We find that most halide motifs (91.6%) in our data set are substantially stabilizing, and their average stabilization energy is significantly larger than that previously obtained for sophisticated protein salt bridges (−15.16 vs −3.66 kcal/mol). Strikingly, nonelectrostatic factors, especially the dispersion potential, rather than the electrostatic aspect, dominate the energetic profile of the pronouncedly charged halide motifs, since the expensive cost for electrostatic desolvation penalty requires being paid off using the income receiving from the favorable Coulomb interactions during the motif formation. In addition, all the energy terms involved in halide motifs, regardless of their electrostatic or nonelectrostatic nature, highly depend on the degree of the motif’s burial in the protein, and the buried halide motifs are generally associated with a high stability. The results presented herein should be of valuable use in establishing a knowledge framework toward understanding the functional implications underlying anion structured in a biological molecule.

Systematic theoretical investigations on the tautomers of thymine in gas phase and solution

Co-reporter:Ji-Cai Fan, Zhi-Cai Shang, Jun Liang, Xiu-Hong Liu, Hong Jin

Journal of Molecular Structure: THEOCHEM 2010 Volume 939(1–3) pp:106-111

Publication Date(Web):15 January 2010

DOI:10.1016/j.theochem.2009.09.047

The tautomers of thymine are systematically calculated using various methods. The order of the relative stability, dipole moment as well as solvent effect of the 13 isomers are investigated. The one-step transition process by proton transfer in gas phase and in solution (H2O or CH3OH), which acts as both proton donor and acceptor, are exhaustively studied, meanwhile, the internal rotation between two related isomers in the gas phase is also investigated. Furthermore, the energy barrier of each transition is calculated and the results show that both H2O and CH3OH could reduce the energy barrier. Comparisons between the activation energies of all the producing processes of each tautomer as well as temperature effect on the producing processes are made. The calculation results also indicated that the diketo is the most stable isomer both in gas phase and in solution, additionally, it is thermodynamically as well as dynamically favored.

Fluorine Bonding — How Does It Work In Protein−Ligand Interactions?

Co-reporter:Peng Zhou, Jianwei Zou, Feifei Tian and Zhicai Shang

Journal of Chemical Information and Modeling 2009 Volume 49(Issue 10) pp:2344-2355

Publication Date(Web):September 29, 2009

DOI:10.1021/ci9002393

Although fluorination of pharmacologically active compounds has long been a common strategy to increase their metabolic stability and membrane permeation, the functionality of protein−ligand interactions involving fluorine atoms (fluorine bonding) was only recently recognized in the chemistry and biology communities. In this study, the geometric characteristics and the energetic behaviors of fluorine bonding were systematically investigated by combining two quite disparate but complementary approaches: X-ray structural analysis and theoretical calculations. We found that the short contacts involving fluorine atoms (generalized fluorine bonding) between proteins and fluorinated ligands are very frequent, and these contacts, compared to those routine hydrogen/halogen bonding, are more similar to sulfur-involved hydrogen bonding observed in proteins. ONIOM-based quantum mechanics/molecular mechanics analysis further revealed that fluorine bonding does play an essential role in protein−ligand binding, albeit the strength of isolated fluorine bonding is quite modest. Furthermore, 14 quantum mechanics (QM) and molecular mechanics (MM) methods were performed to reproduce fluorine bonding energies obtained at the rigorous MP2/aug-cc-pVDZ level of theory, and the results showed that most QM and very few MM methods perform well in the reproducibility; the MPWLYP functional and MMFF94 force field are recommended to study moderate and large fluorine bonding systems, respectively.

Comprehensive comparison of eight statistical modelling methods used in quantitative structure–retention relationship studies for liquid chromatographic retention times of peptides generated by protease digestion of the Escherichia coli proteome

Co-reporter:Peng Zhou, Feifei Tian, Fenglin Lv, Zhicai Shang

Journal of Chromatography A 2009 Volume 1216(Issue 15) pp:3107-3116

Publication Date(Web):10 April 2009

DOI:10.1016/j.chroma.2009.01.086

In this study, we propose a new peptide characterization method that gives attention to both the amino acid composition and the residue local environment. Using this approach, structural characteristics of peptides derived from Escherichia coli proteome were parameterized and, based upon that, the performance profile of eight statistical modelling methods were validated rigorously and compared comprehensively by applying them to modelling relationship between the sequence structure and retention ability for 816 experimentally measured peptides and to predicting normalized retention times for 121,273 unmeasured peptides in liquid chromatography. Results show that the regression models constructed by nonlinear approaches are more robust and predictable but time-consuming than those by linear ones. In these modelling methods, Gaussian process and back-propagation neural network possess the best stability, unbiased ability and predictive power, thus they can be used to accurately model the peptide structure–retention relationships; multiple linear regression and partial least squares regression perform worse compared to nonlinear modelling techniques but they are computationally efficient, so they are promising candidates for solving the qualitative problems involved in massive data. In addition, by investigating the descriptor importance in different models we found that the amino acid composition presents a significantly linear correlation with the retention time of peptides, whereas the residue environment is mainly correlated nonlinearly with peptide retention. The polar Arg and strongly hydrophobic amino acids such as Leu, Ile, Phe, Trp and Val are the critical factors influencing peptide retention behavior.

Side-chain conformational space analysis (SCSA): A multi conformation-based QSAR approach for modeling and prediction of protein–peptide binding affinities

Co-reporter:Peng Zhou;Xiang Chen

Journal of Computer-Aided Molecular Design 2009 Volume 23( Issue 3) pp:

Publication Date(Web):2009 March

DOI:10.1007/s10822-008-9245-0

In this article, the concept of multi conformation-based quantitative structure–activity relationship (MCB-QSAR) is proposed, and based upon that, we describe a new approach called the side-chain conformational space analysis (SCSA) to model and predict protein–peptide binding affinities. In SCSA, multi-conformations (rather than traditional single-conformation) have received much attention, and the statistical average information on multi-conformations of side chains is determined using self-consistent mean field theory based upon side chain rotamer library. Thereby, enthalpy contributions (including electrostatic, steric, hydrophobic interaction and hydrogen bond) and conformational entropy effects to the binding are investigated in terms of occurrence probability of residue rotamers. Then, SCSA was applied into the dataset of 419 HLA-A*0201 binding peptides, and nonbonding contributions of each position in peptide ligands are well determined. For the peptides, the hydrogen bond and electrostatic interactions of the two ends are essential to the binding specificity, van der Waals and hydrophobic interactions of all the positions ensure strong binding affinity, and the loss of conformational entropy at anchor positions partially counteracts other favorable nonbonding effects.

LigEvolutioner, a New Strategy for Modification and Optimization of Lead Compounds in Receptor/Ligand Complexes

Co-reporter:Peng Zhou;Feifei Tian

Chemical Biology & Drug Design 2008 Volume 72( Issue 6) pp:525-532

Publication Date(Web):

DOI:10.1111/j.1747-0285.2008.00733.x

With the number of solved protein/ligand complex 3D structures growing up rapidly in recent years, lead modification and optimization based on the complex structure have received much attention in drug design community. In this study, we propose a novel method LigEvolutioner for the purpose of lead optimization in protein/ligand complexes. Using a fragment substitution strategy in the context of evolutionary algorithm, LigEvolutioner can analyze the complex structures automatically and derive several modification projects that could possibly improve the binding affinity of ligands. For instance, LigEvolutioner was employed to analyze and modify antigenic peptide ligand in human HLA-A*0201/peptide complexes and, as a result, a peptide analogue with potential high affinity was designed. The structure configuration of this modified peptide is consistent with crystal profile and antigen presenting theory. In addition, we have confirmed the validity of LigEvolutioner by systematically comparing it with several widely used scoring methods.

The oxidation of alcohols to aldehydes and ketones with N-bromosuccinimide in polyethylene glycol: an experimental and theoretical study

Co-reporter:Ji-Cai Fan;Zhi-Cai Shang;Jun Liang;Xiu-Hong Liu ;Yang Liu

Journal of Physical Organic Chemistry 2008 Volume 21( Issue 11) pp:945-953

Publication Date(Web):

DOI:10.1002/poc.1404

Abstract

Oxidation of aliphatic and aromatic alcohols has been studied by using N-bromosuccinimide (NBS) as oxidant and polyethylene glycol (PEG) as reaction medium under mild reaction conditions. Temperature and solvent effect are studied. Theoretical study is also done with the Gaussian 98 suite of program and the calculation results are in good accordance with the experimental outcome. This system offers a very clean, convenient, environmentally benign method for the oxidation of alcohols. Copyright © 2008 John Wiley & Sons, Ltd.

L-Proline as an efficient and reusable promoter for the synthesis of coumarins in ionic liquid

Co-reporter:Xiu-hong Liu;Ji-cai Fan;Yang Liu

Journal of Zhejiang University-SCIENCE B 2008 Volume 9( Issue 12) pp:990-995

Publication Date(Web):2008 December

DOI:10.1631/jzus.B0820079

The effect of L-proline as a promoter on the condensation reaction of salicylaldehyde or its derivatives with ethyl acetoacetate in neutral ionic liquid [emim]BF4 was studied. All reactions were carried out under mild reaction conditions and achieved high yields. Moreover, the ionic liquid containing L-proline could be recycled and reused for several times without noticeably decreasing in productivity. The results show that the L-proline-[emim]BF4 system has a potential in contribution to the development of environmentally friendly and inexpensive processes in organic syntheses.

Theoretical study of the oxidation of alcohols to the carbonyl compounds with N-bromosuccinimide and H2O2

Co-reporter:Ji-Cai Fan, Tian-Xing Wu, Zhi-Cai Shang, Jun Liang, Hong Jin

Journal of Molecular Structure: THEOCHEM 2008 Volume 863(1–3) pp:128-132

Publication Date(Web):30 August 2008

DOI:10.1016/j.theochem.2008.05.033

Oxidation of both aliphatic and aromatic alcohols in the presence of N-bromosuccinimide and hydrogen peroxide under transition metal-free conditions has been studied by means of density functional theory (DFT) method. Solvent effect on the reaction is evaluated with the polarizable continuum model (PCM) and is compared with the experimental outcomes. In particular, the reaction mechanism is proposed and proved by theoretical study.

Theoretical study of the mechanism of high-pressure induced 1,3-dipolar cycloadditions of azides with electron-rich olefins

Co-reporter:Ji-Cai Fan, Jun Liang, Yun Wang, Zhi-Cai Shang

Journal of Molecular Structure: THEOCHEM 2007 Volume 821(1–3) pp:145-152

Publication Date(Web):1 November 2007

DOI:10.1016/j.theochem.2007.07.004

The high-pressure induced 1,3-dipolar cycloadditions of azides with electron-rich olefins have been studied by means of density functional theory (DFT) method. It is shown that high-pressure could induce the 1,3-dipolar cycloaddition of azides not only with electron-deficient olefins but also with electron-rich ones. The results derived from the theoretical calculations also indicate that the concerted mechanism is both kinetically and thermodynamically preferred to the stepwise one. In addition, the solvent effects on the stability of the products and transition states are taken into account, and the comparison of the calculated results between the 1,3-dipolar cycloadditions of azides with electron-deficient olefins and electron-rich ones is employed.